On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance
Susanna Fürst,
Zoltán S. Zádori,
Ferenc Zádor,
Kornél Király,
Mihály Balogh,
Szilvia B. László,
Barbara Hutka,
Amir Mohammadzadeh,
Chiara Calabrese,
Anna Rita Galambos,
Pál Riba,
Patrizia Romualdi,
Sándor Benyhe,
Júlia Timár,
Helmut Schmidhammer,
Mariana Spetea,
Mahmoud Al-Khrasani
Affiliations
Susanna Fürst
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Zoltán S. Zádori
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Ferenc Zádor
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Kornél Király
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Mihály Balogh
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Szilvia B. László
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Barbara Hutka
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Amir Mohammadzadeh
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Chiara Calabrese
Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum University of Bologna Via Irnerio 48, 40126 Bologna, Italy
Anna Rita Galambos
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Pál Riba
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Patrizia Romualdi
Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum University of Bologna Via Irnerio 48, 40126 Bologna, Italy
Sándor Benyhe
Institute of Biochemistry, Biological Research Center, Temesvári krt. 62., H- 6726 Szeged, Hungary
Júlia Timár
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Helmut Schmidhammer
Department of Pharmaceutical Chemistry, Institut of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Mariana Spetea
Department of Pharmaceutical Chemistry, Institut of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Mahmoud Al-Khrasani
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
There is growing evidence on the role of peripheral µ-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic treatment with opioid analgesics induces central analgesic tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms, including receptor desensitization, G-protein decoupling, β-arrestin recruitment, and alterations in the expression of peripheral MORs and microbiota have been postulated to contribute to the development of opioid analgesic tolerance. However, these studies are largely focused on central opioid analgesia and tolerance. Accumulated literature supports that peripheral MORs mediate analgesia, but controversial results on the development of peripheral opioid receptors-mediated analgesic tolerance are reported. In this review, we offer evidence on the consequence of the activation of peripheral MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic efficacy and decrease the development of tolerance to opioids at the peripheral sites. We have also addressed the advantages and drawbacks of the activation of peripheral MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central and peripheral analgesic tolerance.
